This application is focused on the design, synthesis and evaluation of potential biological probes and treatment agents for alcohol dependence based on their actions on the nociceptin receptor (NOP receptor). We seek to identify compounds that act as partial agonists at the human NOP receptor. We will utilize a medicinal chemistry approach via de novo design and synthesis of putative NOP receptor ligands through cheminformatics efforts and by accessing compounds from the NIH's MLSCN library to generate novel compounds with high affinity, selectivity, and novel structural scaffolds. Compounds will be tested in various cell-based functional assays and in receptor binding assays. Lead compounds will be further evaluated in pharmacokinetic analyses followed by assessment of their efficacies in (1) electrophysiological assay of rat central amygdala (CeA) GABA release and (2) self-administration of alcohol in dependent rats. Current alcohol addiction pharmacotherapies have shown moderate efficacy and no clinically testable compounds targeting the NOP receptor are in existence today. Our preliminary results describe the identification of a novel and patentable NOP receptor ligand series represented by SR-2319 and SR-2039, with low nanomolar affinity and selectivity over opioid receptor family members. These compound scaffolds, and others that will be created, should prove useful for the development of additional compounds. Our current lead compound, SR-2319, like the commonly used agonist Ro64-6198, does not possess intrinsic hedonic value in rewarding brain stimulation in rats as evaluated in the intracranial self-stimulation (ICSS) paradigm. We therefore believe that targeting of the NOP receptor will not likely be associated with abuse liability. In sum, we aim to take a systematic and multi-disciplinary drug discovery strategy to identify NOP partial agonist(s) for the potential use in alcohol dependence. PUBLIC HEALTH RELEVANCE: Alcohol dependence and abuse represents a considerable health and economic burden on society with available pharmacotherapies demonstrating insufficient efficacy. Our goal is to generate a novel therapeutic entity to be used in alcohol research and with the potential of ultimately translating into the clinic as efficacious treatments for alcohol dependence and abuse.